1. Field of the Invention
The present invention relates to specific compounds designed to inhibit cell growth signaling. In particular, PtdIns-3-kinase anti-metabolites are rationally designed to provide compounds that inhibit cell differentiation and/or cell proliferation, and/or which promote apoptosis by antagonizing myo-inositol cell growth signaling. The present invention also relates to therapeutic methods, e.g., treatment of cancer, including the administration of the compounds according to the invention.
2. Background of the Invention
For mammalian cells to survive, they must be able to respond rapidly to changes in their environment. Furthermore, for cells to reproduce and carry out other cooperative functions, they must be able to communicate efficiently with each other. Cells most frequently adapt to their environment and communicate with one another by means of chemical signals. An important feature of these signaling mechanisms is that in almost all cases a cell is able to detect a chemical signal without it being necessary for the chemical messenger itself to enter the cell. This permits the cell to maintain the homeostasis of its internal environment, thereby permitting the cell to respond to its external environment without being adversely affected by it.
These sensing functions are carried out by a variety of receptors, which are dispersed on the outer surface of the cell and function as xe2x80x9cmolecular antennaexe2x80x9d. These receptors detect an incoming messenger and activate a signal pathway that ultimately regulates a cellular process such as secretion, contraction, metabolism or growth. In the cell""s cellular plasma membrane, transduction mechanisms translate external signals into internal signals, which are then carried throughout the interior of the cell by chemicals known as xe2x80x9csecond messengers.xe2x80x9d
In molecular terms, the process depends on a series of proteins within the cellular plasma membrane, each of which transmits information by inducing a conformational change in the protein next in line. At some point, the information is assigned to small molecules or even to ions within the cell""s cytoplasm, which serve as the above-mentioned second messengers. The diffusion of the second messengers enables a signal to propagate rapidly throughout the cell.
Several major signal pathways are now known, but two seem to be of primary importance. One employs cyclic nucleotides as second messengers. These cyclic nucleotides activate a number of proteins inside the cell, which then cause a specific cellular response. The other major pathway employs a combination of second messengers that includes calcium ions as well as two substances whose origin is remarkable: myo-inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). These compounds are cannibalized from the plasma membrane itself, by enzymes which are activated by specific cellular membrane receptors. However, this pathway requires that myo-inositol, in its non-phosphorylated form, be initially synthesized by the cell from glucose or obtained from the extracellular environment. Recently, another phosphatidylinositol signaling pathway has been identified and linked to the action of some growth factors and oncogenes. Phosphatidylinositol-3xe2x80x2-kinase (also designated type 1 phosphatidylinositol kinase) is found associated with a number of protein tyrosine kinases including the ligand-activated receptors for insulin, platelet derived growth factor (PDGF), epidermal growth factor (EGF), and colony-stimulating factor-1 (CSF-1) as well as proto-oncogene and oncogene tyrosine kinases (Y. Fukui et al., Oncogene Res., 4, 283 (1989)). This enzyme phosphorylates the D-3 position of the myo-inositol ring of phosphatidylinositols to give a class of phosphafdylinositol-3xe2x80x2-phosphates that are not substrates for hydrolysis by phosphatidylinositol phospholipase C. Accordingly, these compounds apparently exert their signaling action independently of the inositol phosphate pathway.
Based on the potential effects thereof on cell proliferation, differentiation and apoptosis, it would be beneficial if compounds could be obtained which selectively block phosphatidylinositol signaling pathways. More specifically, it would be beneficial if compounds could be obtained which antagonize myo-inositol metabolites produced by PtdIns-3-Kinase. Such compounds have significant therapeutic potential, in particular for treatment of cancer and other conditions involving abnormal cell differentiation and proliferation. Compounds having improved selectivity, solubility and stability are particularly desirable.
It is an object of the invention to provide novel compounds which inhibit the phosphatidylinositol signaling pathway.
It is a more specific object of the invention to provide novel compounds which are antagonistic of myo-inositol metabolites provided by PtdIns-3-Kinase.
It is an even more specific object of the invention to provide novel analogs of 3-deoxy-D-myo-inositol which inhibit the phosphatidylinisitol signaling pathway.
It is still a more specific object of the invention to provide compounds having the formulae (I) and (II) set forth below: 
wherein X is O or CH2; R1 and R2 are individually, (C1-C25) alkyl, (C6-C10) aryl, (C3-C8) cycloalkyl, (C2-C22) alkenyl, (C5-C8) cycloalkenyl, (C7-C32) aralkyl, (C7-C32) alkylaryl aralkenyl, (C9-C32) alkenylaryl or C(O)R3; and R3 is (C1-C25) alkyl, (C6-C10) aryl, (C3-C8) cycloalkyl, (C2-C22) alkenyl, (C5-C8) cycloalkenyl, (C7-C32) aralkyl, (C7-C32) alkylaryl, (C9-C32) aralkenyl or (C9-C32) alkenylaryl, with the proviso that when X is O, R3 is not (C15) alkyl; R4 and R5 are individually hydrogen or a phosphate group; or when R4 or R5 is not hydrogen, a pharmaceutically acceptable salt thereof; and 
wherein X is O or CH2,; R1 and R2 are individually, (C1-C25) alkyl, (C6-C10) aryl, (C3-C8) cycloalkyl, (C2-C22) alkenyl, (C5-C8) cycloalkenyl, (C7-C32) aralkyl, (C7-C32) alkylary aralkenyl, (C9-C32) alkenylaryl or C(O)R3; and R3 is (C1-C25) alkyl, (C6-C10) aryl, (C3-C8) cycloalkyl, (C2-C22) alkenyl, (C5-C8) cycloalkenyl, (C7-C32) aralkyl, (C7-C32) alkylary aralkenyl or (C9-C32) alkenylaryl; R4 and R5 are individually hydrogen or a phosphate group; or when R4 or R5 is not hydrogen, a pharmaceutically acceptable salt thereof.
It is a more specific object of the invention to treat cancer by the administration of at least one compound of the formulae (I) or (II): 
wherein X is O or CH2; R1 and R2 are individually, (C1-C25) alkyl, (C6-C10) aryl, (C3-C8) cycloalkyl, (C2-C22) alkenyl, (C5-C8) cycloalkenyl, (C7-C32) aralkyl, (C7-C32) alkylary aralkenyl, (C9-C32) alkenylaryl or C(O)R3; and R3 is (C1-C25) alkyl, (C6-C10) aryl, (C3-C8) cycloalkyl, (C2-C22) alkenyl, (C5-C8) cycloalkenyl, (C7-C32) aralkyl, (C7-C32) alkylaryl, (C9-C32) aralkenyl or (C9-C32) alkenylaryl, with the proviso that when X is O, R3 is not (C15) alkyl; R4 and R5 are individually hydrogen or a phosphate group; or when R4 or R5 is not hydrogen, a pharmaceutically acceptable salt thereof; and 
wherein X is O or CH2; R1 and R are individually, (C1-C25) alkyl, (C6-C10) aryl, (C3-C8) cycloalkyl, (C2-C22) alkenyl, (C5-C8) cycloalkenyl, (C7-C32) aralkyl, (C7-C32) alkylaryl, (C9-C32) aralkenyl, (C9-C32) alkenylaryl or C(O)R3; and R3 is (C1-C25) alkyl, (C6-C10)) aryl, (C3-C8) cycloalkyl, (C2-C22) alkenyl, (C5-C8) cycloalkenyl, (C7-C32) aralkyl, (C7-C32) alkylaryl, (C9-C32) aralkenyl or (C9-C32) alkenylaryl; R4 and R5 are individually hydrogen or a phosphate group; or when R4 or R5 is not hydrogen, a pharmaceutically acceptable salt thereof.
It is another object of the invention to provide pharmaceutical compositions comprising at least one novel compound that inhibits the phosphatidylinositol signaling pathway, and more preferably a compound that antagonizes myo-inositol metabolites produced by PtdIns-3-Kinase.
It is a more specific object of the invention to provide pharmaceutical compositions that comprise at least one compound having the formulae (I) or (II): 
wherein X is O or CH2; R1 and R2 are individually, (C1-C25) alkyl, (C6-C10) aryl, (C3-C8) cycloalkyl, (C2-C22) alkenyl, (C5-C8) cycloalkenyl, (C7-C32) aralkyl, (C7-C32) alkylaryl, (C9-C32) aralkenyl, (C9-C32) alkenylaryl or C(O)R3; and R3 is (C1-C25) alkyl, (C6-C10) aryl, (C3-C8) cycloalkyl, (C2-C22) alkenyl, (C5-C8) cycloalkenyl, (C7-C32) aralkyl, (C7-C32) alkylary, (C9-C32) aralkenyl or (C9-C32) alkenylaryl, with the proviso that when X is O, R3 is not (C15) alkyl; R4 and R5 are individually hydrogen or a phosphate group; or when R4 or R5 is not hydrogen, a pharmaceutically acceptable salt thereof; or 
wherein X is O or CH2; R1 and R2 are individually, (C19-C25) alkyl, (C6-C10) aryl, (C3-C8) cycloalkyl, (C2-C22) alkenyl, (C5-C8) cycloalkenyl, (C7-C32) aralkyl, (C7-C32) alkylary, (C9-C32) aralkenyl, (C9-C32) alkenylaryl or C(O)R3; and R3 is (C1-C25) alkyl, (C6-C10) aryl, (C3-C8) cycloalkyl, (C2-C22) alkenyl, (C5-C8) cycloalkenyl, (C7-C32) aralkyl, (C7-C32) alkylary, (C9-C32) aralkenyl or (C9-C32) alkenylaryl; R4 and R5 are individually hydrogen or a phosphate group; or when R4 or R5 is not hydrogen, a pharmaceutically acceptable salt thereof; which inhibit the phosphatidylinositol signaling pathway and thereby inhibit cell proliferation and/or differentiation and/or promote apoptosis.
It is another object of the invention to provide novel therapies based on inhibiting in vivo the phosphatidylinositol signaling pathway.
It is a more specific object of the invention to provide novel therapies that result in the inhibition of cell proliferation and/or differentiation and/or the promotion of cell apoptosis comprising the administration of a compound that antagonizes myo-inositol cell growth signaling.
It is an even more specific object of the invention to provide novel therapies that result in the inhibition of cell proliferation and/or differentiation and/or promotion of cell apoptosis by the administration of a compound having formulae (I) or (II): 
wherein X is O or CH2; R1 and R2 are individually, (C1-C25) alkyl, (C6-C10) aryl, (C3-C8) cycloalkyl, (C2-C22) alkenyl, (C5-C8) cycloalkenyl, (C7-C32) aralkyl, (C7-C32) alkylary, (C9-C32) aralkenyl, (C9-C32) alkenylaryl or C(O)R3; and R3 is (C1-C25) alkyl, (C6-C10) aryl, (C3-C8) cycloalkyl, (C2-C22) alkenyl, (C5-C8) cycloalkenyl, (C7-C32) aralkyl, (C7-C32) alkylaryl, (C9-C32) aralkenyl or (C9-C32) alkenylaryl, with the proviso that when X is O, R3 is not (C15) alkyl; R4 and R5 are individually hydrogen or a phosphate group; or when R4 or R is not hydrogen, a pharmaceutically acceptable salt thereof; or 
wherein X is O or CH2; R1 and R2 are individually, (C1-C25) alkyl, (C6-C10) aryl, (C3-C8) cycloalkyl, (C2-C22) alkenyl, (C5-C8) cycloalkenyl, (C7-C32) aralkyl, (C7-C32) alkylaryl, (C9-C32) aralkenyl, (C9-C32) alkenylaryl or C(O)R3; and R3 is (C1-C25) alkyl, (C6-C10) aryl, (C3-C8) cycloalkyl, (C2-C22) alkenyl, (C5-C8) cycloalkenyl, (C7-C32) aralkyl, (C7-C32) alkylaryl, (C9-C32) aralkenyl or (C9-C32) alkenylaryl; R4 and R5 are individually hydrogen or a phosphate group; or when R4 or R5 is not hydrogen, a pharmaceutically acceptable salt thereof.
In a preferred embodiment, such therapies will comprise treatment of cancer and other neoplastic conditions and/or will comprise treatment of arthritis, inflamation or modulation of platelet aggregation.